Methods of using substituted flavones for treating bone disorders

Abstract

Provided herein are methods of using 4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(methylcarbamate) and derivatives thereof for treating or preventing a bone disorder. The methods include administering to the subject an effective amount of a compound of Formula I or a pharmaceutical composition as described herein. The bone disorder can include, for example, osteoporosis. Also provided herein are methods of inhibiting asparagine endopeptidase (AEP) activity in a cell and methods of promoting bone growth, increasing bone density, or increasing bone strength in a subject. Novel mechanisms of action in treating and preventing bone disorders are provided herein.

What is claimed is: 
     
         1 . A method of treating or preventing a bone disorder in a subject, comprising administering to the subject an effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         X is O, S, or NH; 
         U and Y are each independently O, S, NH, Nalkyl, or CH 2 ; 
         Z is hydrogen, amino, diaminoalkyl, or heterocyclyl optionally substituted with one or more, the same or different, R 15 ; 
         R 1  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R 1  is optionally substituted with one or more, the same or different, R 15 ; 
         R 2  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2  is optionally substituted with one or more, the same or different, R 15 ; 
         R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are each independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are optionally substituted with one or more, the same or different, R 15 ; 
         each R 15  is independently selected from the group consisting of alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, and aryl, wherein R 15  is optionally substituted with one or more, the same or different, R 16 ; and 
         each R 16  is independently selected from the group consisting of halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl. 
       
     
     
         2 . The method of  claim 1 , wherein U and Y are NH or Nalkyl. 
     
     
         3 . The method of  claim 1 , wherein U and Y are O. 
     
     
         4 . The method of  claim 1 , wherein R 1  and R 2  are alkyl. 
     
     
         5 . The method of  claim 1 , wherein the compound is selected from the group consisting of
 4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(methylcarbamate);   4-oxo-2-phenyl-4H-chromene-7,8-diyl dipropionate;   4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(2,2-dimethylpropanoate);   diethyl (4-oxo-2-phenyl-4H-chromene-7,8-diyl) dicarbonate;   4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(ethylcarbamate);   4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(dimethylcarbamate); and   4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(3-methylbutanoate) or salts thereof.   
     
     
         6 . The method of  claim 1 , wherein the bone disorder comprises a bone disorder associated with abnormally high bone catabolism. 
     
     
         7 . The method of  claim 1 , wherein the bone disorder is osteoporosis, osteopenia, Paget's disease, bone metastasis, osteogenesis imperfecta, a metastatic bone disease, or a metabolic bone disease. 
     
     
         8 . The method of  claim 1 , further comprising administering an additional active agent, wherein the additional active agent comprises an anti-osteoporosis agent or CF3CN. 
     
     
         9 . The method of  claim 8 , wherein the anti-osteoporosis agent comprises one or more of a bisphosphonate, a RANK-L inhibitor, a parathyroid hormone, a monoclonal antibody, estrogen, and calcitonin. 
     
     
         10 . The method of  claim 1 , wherein the compound is administered orally. 
     
     
         11 . The method of  claim 1 , further comprising selecting a subject with or at risk of developing a bone disorder or experiencing bone loss. 
     
     
         12 . A method of inhibiting asparagine endopeptidase (AEP) activity in a cell, comprising contacting the cell with an effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         X is O, S, or NH; 
         U and Y are each independently O, S, NH, Nalkyl, or CH 2 ; 
         Z is hydrogen, amino, diaminoalkyl, or heterocyclyl optionally substituted with one or more, the same or different, R 15 ; 
         R 1  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R 1  is optionally substituted with one or more, the same or different, R 15 ; 
         R 2  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2  is optionally substituted with one or more, the same or different, R 15 ; 
         R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are each independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are optionally substituted with one or more, the same or different, R 15 ; 
         each R 15  is independently selected from the group consisting of alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, and aryl, wherein R 15  is optionally substituted with one or more, the same or different, R 16 ; and 
         each R 16  is independently selected from the group consisting of halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl. 
       
     
     
         13 . The method of  claim 12 , wherein the compound is selected from the group consisting of
 4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(methylcarbamate);   4-oxo-2-phenyl-4H-chromene-7,8-diyl dipropionate;   4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(2,2-dimethylpropanoate);   diethyl (4-oxo-2-phenyl-4H-chromene-7,8-diyl) dicarbonate;   4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(ethylcarbamate);   4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(dimethylcarbamate); and   4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(3-methylbutanoate) or salts thereof.   
     
     
         14 . The method of  claim 12 , wherein the contacting is performed in vivo. 
     
     
         15 . The method of  claim 12 , wherein the contacting is performed in vitro. 
     
     
         16 . The method of  claim 12 , further comprising selecting a subject with or at risk of developing a bone disorder or experiencing bone loss. 
     
     
         17 . The method of  claim 12 , wherein the contacting increases osteoprotegerin (OPG) levels in the cell as compared to an untreated cell. 
     
     
         18 . The method of  claim 12 , wherein the contacting reduces trabecular bone loss induced by ovariectomy (OVX). 
     
     
         19 . The method of  claim 12 , wherein the contacting inhibits RANK-L-induced osteoclastogenesis. 
     
     
         20 . A method of promoting bone growth, increasing bone density, or increasing bone strength in a subject, comprising
 administering to the subject an effective amount of a compound of Formula I   
       
         
           
           
               
               
           
         
         or a salt thereof, wherein: 
         X is O, S, or NH; 
         U and Y are each independently O, S, NH, Nalkyl, or CH 2 ; 
         Z is hydrogen, amino, diaminoalkyl, or heterocyclyl optionally substituted with one or more, the same or different, R 15 ; 
         R 1  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R 1  is optionally substituted with one or more, the same or different, R 15 ; 
         R 2  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2  is optionally substituted with one or more, the same or different, R 15 ; 
         R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are each independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are optionally substituted with one or more, the same or different, R 15 ; 
         each R 15  is independently selected from the group consisting of alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, and aryl, wherein R 15  is optionally substituted with one or more, the same or different, R 16 ; and 
         each R 16  is independently selected from the group consisting of halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, and heterocyclyl.